The present invention relates to the preparation of infection-resistant materials for use on or within a human or animal body and more particularly to an improved method of preparing infection-resistant materials wherein antimicrobial agents, and preferably metal salts of anti-microbial agents, are incorporated directly into various polymeric materials, including hydrophobic polymeric materials.
Infection is a common complication occasioned from any injury, surgical procedure, or introduction of foreign material, such as a prosthetic device, into a human or animal body. Various techniques and means for alleviating infection, such as topical application of antibiotics, systemic administration of antibiotics, and maintenance of sterility of the operating surroundings, instruments, bandages, etc., are in common use. However, these techniques have not been particularly effective in preventing infection associated with in-dwelling, or surgically implanted, devices intended to remain in the body, or in direct contact with the body, for an extended period of time.
Prior U.S. patent application for Ser. Nos. 605,792 and 605,793, filed on Apr. 30, 1984 and assigned to the assignee hereof, now U.S. Pat. No. 4,563,485, issued Jan. 7, 1986 and U.S. Pat. No. 4,581,028, issued Apr. 8, 1986 respectively, discuss at length the problems associated with in-dwelling and surgically implanted devices wherein long-term infection preventive ability is desired. The aforementioned applications for letters patent are hereby cross-referenced and their entire disclosures are incorporated herein by reference. Briefly, the referenced patent applications are directed to the incorporation of metal salts of sulfonamides or nalidixic acid derivatives and metal salts of nalidixic acid derivatives into natural or synthetic polymeric materials by treating the polymeric materials with an aqueous solution or suspension of the antimicrobial agent. In order to provide adequate absorption or adherence of the antimicrobial agent within the polymeric materials, they are preliminarily treated or coated with gelatin or albumin or a surfactant, such as tridodecylmethyl ammonium chloride. The materials created by the incorporation of the above-referenced antimicrobial agents are ideally suited for body-invasive uses such as vascular grafts, heart valves, bone and joint replacements, etc.
Prevention of infection in vascular reconstructive surgery, in particular, has been the subject of much study in view of the high mortality rate, or catastrophic effects, should infection occur. Typically, systemic antibiotics are administered and the graft site is locally irrigated with an antibiotic solution. The graft is also soaked in an aqueous solution of an antibiotic immediately prior to implantation. However, these techniques have not proven to be completely effective due to the brief residence of antibacterial agents at the implantation site. Moreover, due to the ineffectiveness of known techniques, use of prosthetic grafts in contaminated wounds of trauma victims is interdicted due to lack of anti-bacterial action at the graft site. Incorporation of antibiotics in the graft material, as discussed above, would yield a higher concentration of antibiotic agent at the graft site and would permit slow release of the agent to provide a prolonged concentration of antibiotic at the graft site.
The common practice in the prior art is to bond the antibiotic to a coating on, for example, Dacron polyester or polytetrafluoroethylene (Teflon) graft materials. Known coatings include gelatin, albumin, graphite-benzalkonium chloride and cationic surfactants such as tridodecylmethylammonium chloride (TDMAC). In fact, it was heretofore believed that it was necessary to coat the hydrophobic materials (e.g., PTFE) in order to bond an antibacterial agent thereto.
The coatings, such as TDMAC, present a cationic surface which bonds the anionic antibiotic. The antibiotic is, nevertheless, rapidly dissipated in the body fluids. A certain amount of antibiotic, however, does remain in the coating until the coating dissipates from the substrate material. Adverse effects, such as toxicity and thrombogenesis, are possible. In particular, the cationic coating which is present after the anionic antibiotic has been absorbed into the body may be thrombogenic. A further disadvantage of the coated grafts is that they are inconvenient to use. The manufacturers of such grafts provide them with the coating, but not with the antibiotic. Thus, the grafts must be soaked in an aqueous antibiotic solution at the operating table.